Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy

Figures & data

Figure 1 Flow chart showing selection of literature.

Abbreviation: DDI, drug–drug interaction.

Figure 2 Metabolic profiles of P2Y₁₂ inhibitors.

Abbreviations: CES1, carboxylesterase 1; CES2, carboxylesterase 2; CYP, cytochrome P450; OATP1B1, organic anion transporter family 1B1; P-gp, P-glycoprotein; PON1, Paraoxonase-1.

Table 1 Summary of clopidogrel-associated drug-drug interactions

Circumstances	Comedications	Implications and risk management
1. Clopidogrel comedicated as a precipitant drug	Statins	Clopidogrel has a clinically relevant and significant DDI with cerivastatin instead of other statins. Simvastatin doses greater than 40 mg should be avoided in patients receiving ticagrelor.^Citation14^–^Citation21
	Insulinotropic agents	Clopidogrel should not be comedicated with repaglinide in order to avoid occurrence of potential hypoglycemic events. Ticagrelor may be an alternative to clopidogrel in patients on repaglinide therapy. Nateglinide and mitiglinide may be alternatives to repaglinide when patients are concomitantly using clopidogrel.^Citation15,Citation22,Citation23
	Ferulic acid	Close monitoring for potential drug interactions may be necessary in patients who are receiving combined therapy with clopidogrel and ferulic acid-containing herbs, eg, Danggui (Angelicae sinensis) and Chuangxiong (Rhizoma chuanxiong).^Citation25
	Sibutramine	Careful treatment planning is required when clopidogrel is comedicated with sibutramine, especially in patients with a CYP2B6 functional deficit genotype.^Citation28,Citation29
	Efavirenz	Clopidogrel may decrease elimination of efavirenz in HIV patients and therefore increase adverse effects of efavirenz, especially in patients with the CYP2B6*6 genotype. Combinations like efavirenz-ticagrelor may be a better choice.^Citation33,Citation34
	CYP2C19 substrates	Clinicians should pay more attention to the possible interactions of clopidogrel and substrate drugs of CYP2C19 because the prevalence of extensive metabolizers of CYP2C19 exceeds 50% in the population. Prasugrel and ticagrelor would not cause a clinically relevant interaction with CYP2C19 substrates.^Citation27,Citation36
2. Clopidogrel comedicated as an object drug
• Low efficacy of clopidogrel treatment would be anticipated	Omeprazole, esomeprazole	Clinicians should avoid prescribing omeprazole and esomeprazole in patients taking clopidogrel. The potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by using pantoprazole, dexlansoprazole, or rabeprazole. Clopidogrel-esomeprazole DDI can be diminished by increasing the clopidogrel dose to 150 mg or replacing esomeprazole with ranitidine or famotidine. Prasugrel may be an alternative that can escape the adverse DDIs induced by PPIs.^Citation37^–^Citation47
	Morphine	Coadministration of morphine is best avoided. Caution should be exercised in STEMI patients receiving morphine. Cangrelor, an intravenously administered direct-acting P2Y12 receptor inhibitor, might be an ideal choice in STEMI patients receiving morphine.^Citation49,Citation50
	Grapefruit juice	Use of grapefruit juice is best avoided during clopidogrel therapy, and both clinicians and patients should know the enhanced antiplatelet effect of ticagrelor in the presence of grapefruit juice to avoid the risk of potential bleeding events.^Citation93,Citation94
	Scutellarin	Potential herb-drug interaction between scutellarin and clopidogrel should be borne in mind in clinical use to avoid a reduced antiplatelet effect.^Citation51
	Fluoxetine	Combination use of fluoxetine and clopidogrel should be avoided. Venlafaxine may be an alternative antidepressant comedicated with clopidogrel. Combination therapy of ticagrelor and venlafaxine is an alternative regimen.^Citation52,Citation53
• Low efficacy of clopidogrel would be anticipated	Azole antifungal agents	Combination of clopidogrel and azole antifungal agents like ketoconazole and itraconazole should be avoided. Prasugrel is an alternative when comedicating with azole antifungal agents. Pharmacogenetic screening of CYP3A5*3 should be performed prior to initiating combination therapy with clopidogrel and CYP3A inhibitors.^Citation54^–^Citation56
	Some CCBs	Combination use of clopidogrel and amlodipine should be avoided. When concurrent treatment with clopidogrel and a CCB is initiated, close therapeutic monitoring is needed to prevent a potentially poor response to clopidogrel, especially in patients with a mutant CYP3A4*1G gene.^Citation57^–^Citation59
	Sulfonylureas	Ticagrelor should be considered and clopidogrel should be avoided when initiating combination therapy of sulfonylureas and P2Y12 receptor inhibitors.^Citation61,Citation62
	Ritonavir	Avoid combinations such as ritonavir-clopidogrel and ritonavir-prasugrel (CYP3A4-mediated inhibition by ritonavir and a potentially lower antiplatelet effect) and clopidogrel-efavirenz (CYP2B6-mediated inhibition by clopidogrel and potentially increased efavirenz toxicity); choose combinations such as efavirenz-ticagrelor and ritonavir-ticagrelor since ticagrelor does not require metabolic activation; theoretically, nevirapine may enhance the metabolic activation of clopidogrel and offset the adverse DDI between clopidogrel and antiretroviral medications with inhibitory effects on CYP3A4.^Citation7,Citation34,Citation63,Citation64
• Augmented antiplatelet effects of clopidogrel arising from pharmacokinetic DDIs would be anticipated	Aspirin	The influence of aspirin on pharmacodynamics of clopidogrel is comprehensive. In addition to having a purely synergistic pharmacodynamic effect, the DDI mechanism may also involve the balance of aspirin’s “advantageous” inducible effects on CYP2C19 and PON1 and “disadvantageous” inducible effects on P-gp. Evidence from pharmacokinetic DDI studies provides a new basis for dual therapy with clopidogrel and aspirin.^Citation66^–^Citation72
	Curcumin St John’s wort Cyclosporine	Curcumin may potentially enhance the efficacy of clopidogrel. Further studies are needed to confirm the DDI issue.^Citation73,Citation74 St John’s wort may be a future therapeutic option to increase the antiplatelet effect of clopidogrel in hyporesponders.^Citation75,Citation76 The cyclosporine-clopidogrel DDI risk differs between animal models. A follow-up clinical study is needed to explore the relevance of this remarkable species difference in the P-gp-mediated DDI between clyclosporine and clopidogrel. The magnitude of the effect of cyclosporine on the pharmacokinetics of ticagrelor does not warrant dose adjustment of ticagrelor.^Citation77^–^Citation79
	Rifampicin	Combination use of rifampicin would augment the antiplatelet efficacy of clopidogrel; however, it is necessary to know the increased risk of clopidogrel-associated bleeding. Coadministration of rifampicin with ticagrelor should be discouraged. Dose adjustment is not necessary when prasugrel is administered with rifampicin.^Citation80^–^Citation82
	ACEIs	Combination therapy of clopidogrel and an ACEI may be favorable in hyporesponsive patients receiving clopidogrel due to enhanced antiplatelet effects by ACEI; however, vigilance is required regarding an elevated risk of bleeding events. Aspirin, prasugrel, and ticagrelor are not metabolized by CES1 and are therefore not prone to CES1-mediated DDI.^Citation83

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; CYP, cytochrome P450; CES1, carboxylesterase 1; DDI, drug–drug interaction; HIV, human immunodeficiency virus; P-gp, P-glycoprotein; PPIs, proton pump inhibitors; PON1, paraoxonase-1; STEMI, ST-segment elevation myocardial infarction.

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